Synthesis of a [¹⁴C]‐steroid intermediate: an application of a nonstabilized Horner–Wadsworth–Emmons olefination approach

Abstract

Radiolabeled steroid derivative 1 was successfully prepared using a Horner-Wadsworth-Emmons approach: a [(14) C]-label was efficiently incorporated into the C-18 position of the molecule. Previously published procedures employing other olefination methods are either not applicable due to unavailability of [(14) C]-precursors or suffer from poor reactivity.

New radical methods for the potential synthesis of carbon‐13 and carbon‐14 labeled complex products

“…The use of three equivalents of the α,β unsaturated ketone, 34 , somewhat precludes the use of isotopic carbon labels in this portion of the steroid, unless the reaction conditions are modified to reduce the number of equivalents of the α,β‐unsaturated ketone to close to one. Alternatively, one could imagine using Wittig or Horner‐Wadsworth‐Emmons olefination chemistry on the corresponding ketone to introduce a carbon‐13 or carbon‐14 at the terminal end of the alkene as demonstrated by Rivera and co‐workers, followed by radical chemistry to generate the labeled steroid product, 35 , in only two isotopically labeled steps …”

“…2,3 The use of three equivalents of the α,β unsaturated ketone, 34, somewhat precludes the use of isotopic carbon labels in this portion of the steroid, unless the reaction conditions are modified to reduce the number of equivalents of the α,β-unsaturated ketone to close to one. Alternatively, one could imagine using Wittig or Horner-Wadsworth-Emmons olefination chemistry on the corresponding ketone to introduce a carbon-13 or carbon-14 at the terminal end SCHEME 3 Stable-isotope labeled hydromethylation of pregabalin precursor 1 SCHEME 4 Preparation of carbon-14 labeled derivative of rotenone, 18 1 SCHEME 5 Mechanism for the radical isotopic hydromethylation of an unactivated olefin 1 of the alkene as demonstrated by Rivera and co-workers, 5 followed by radical chemistry to generate the labeled steroid product, 35, in only two isotopically labeled steps. 2,3 This olefin cross-coupling methodology was demonstrated in the isotopic labeling with vinyl sulfone, 37, as shown in Scheme 9.…”